Asthma is an inflammatory disease, and T cells are essential for initiating and maintaining the asthmatic inflammatory response. Currently, the ultimate goal in the treatment of asthma is to decrease inflammation, but the treatments (e.g., corticosteriods) commonly used are restricted by deleterious side effects, even when administered by aerosol. Immunomodulatory therapies directed at molecular targets involved with the pathogenesis of asthma have several potential advantages including less intensive use of medications and fewer side effects. The necessity for early and precise suppression of pulmonary inflammation compels an aggressive approach to understanding the mechanisms of T cell activation. The long term goal of this proposal is to decipher the molecular pathways of T cell activation that participate in the pathogenesis of asthma. We were the first to publish that blockade of T cell costimulation inhibits pulmonary inflammation and airway hyperresponsiveness in murine model of allergic asthma. Our hypothesis is: Pulmonary inflammation resulting from chronic aeroallergen exposure is associated with altered costimulatory (B7/CD28 and CTLA4) pathways involving antigen specific T cells. To test this hypothesis, we will employ in vivo and in vitro models, including an adoptive transfer model of allergic asthma with mutant mice which express a transgene specific for the ovalbumin (OVA) allergen and knock out mice deficient in costimulatory molecules. To examine the cellular and molecular mechanisms governing costimulatory effects related to allergic asthma, Aim I will develop a strategy to determine whether the B7-1 and B7-2 costimulatory ligands have different functions in the pathogenesis of pulmonary inflammation. Aim II will investigate the cellular mechanism by which the CTLA4 receptor limits pulmonary allergic responses. Aim III will determine the molecular mechanisms which control CTLA4 expression. Our published and preliminary results indicate that B7/CD28 and B7/CTLA4 costimulatory signals are important positive and negative regulators of pulmonary inflammation, respectively. The mechanisms that regulate B7/CD28 and B7/CTLA4 functions may be key targets for the design of novel therapies to treat asthma. The present study is designed to elucidate these mechanisms.